What every physician needs to know:

Pulmonary Langerhans cell histiocytosis (PLCH) is a rare and typically smoking-related interstitial lung disease that is characterized by proliferation of Langerhans cells and associated nodular and cystic changes in the lung parenchyma.

Classification

PLCH encountered in adults should be distinguished from other forms of Langerhans cell histiocytosis, particularly those encountered in children, which are usually multi-system clonal disorders.

Are you sure your patient has pulmonary Langerhans cell histiocytosis? What should you expect to find?

Approximately two-thirds of patients with PLCH are symptomatic at presentation, with the most common symptoms consisting of dyspnea and cough. Constitutional symptoms, including fever, sweats, and weight loss, are encountered in 15-20% of patients. Pneumothorax is the mode of presentation in about 15% of patients. Uncommon features include diabetes insipidus, skin lesions, and pain due to bone involvement.

Beware: there are other diseases that can mimic pulmonary Langerhans cell histiocytosis:

Other diseases that can be associated with diffuse cystic changes in the lungs and can be confused with PLCH include pulmonary lymphangioleiomyomatosis (LAM), Birt-Hogg-Dube syndrome, lymphoid interstitial pneumonia (LIP), amyloidosis, and emphysema.

More than 90% of adults diagnosed with PLCH are current or previous cigarette smokers. Age at the time of presentation is usually twenty to fifty years. There is no gender predilection. Although PLCH has generally been considered an acquired benign disorder, recent evidence suggests that at least a subset of these patients have a clonal proliferative disorder of mutated cells including the BRAF V600E mutation.

Which individuals are at greatest risk of developing pulmonary Langerhans cell histiocytosis?

The main risk factor for developing adult PLCH is cigarette smoking. No other risk factors have been identified.

What laboratory studies should you order to help make the diagnosis, and how should you interpret the results?

Routine laboratory studies are not useful in the diagnosis of PLCH.

What imaging studies will be helpful in making or excluding the diagnosis of pulmonary Langerhans cell histiocytosis?

High-resolution CT scan of the chest should be obtained in any patient suspected of PLCH and typically demonstrates nodular and/or irregularly shaped cystic and cavitary lesions predominantly in the upper- and mid-lung zones (Figure 1A) with relative sparing of the lung bases (Figure 1B) (Figure 2). Architectural distortion consisting of coarse reticular opacities are commonly seen in the intervening lung parenchyma. By contrast, cystic lesions of pulmonary LAM are generally round and are diffusely distributed throughout the lungs with no zonal predominance or sparing.

Figure 1A.

A high-resolution CT image of the upper lung field in a forty-eight-year-old female smoker with PLCH reveals cystic and nodular lesions in both lungs.

Figure 1B.

A high-resolution CT image of the upper lung field in a forty-eight-year-old female smoker with PLCH demonstrates relative sparing of the lung bases.

Figure 2.

A high-resolution CT coronal image in a thirty-two-year-old female smoker with PLCH demonstrates advanced irregular cystic changes in the upper- and mid-lung fields with relative sparing of the lung bases.

Chest radiography, which is almost always abnormal, reveals interstitial lung infiltrates predominantly in the upper- and mid-lung fields. However, the nodules and cysts characteristic of PLCH are difficult to discern on chest radiography.

What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of pulmonary Langerhans cell histiocytosis?

Pulmonary function tests reveal variable results but show an obstructive or mixed pattern more often than a restrictive pattern. About 70% of patients with PLCH have a reduced diffusion capacity. Up to 20% of patients may have normal pulmonary function tests at presentation.

What diagnostic procedures will be helpful in making or excluding the diagnosis of pulmonary Langerhans cell histiocytosis?

Bronchoscopy with transbronchial biopsy and bronchoalveolar lavage (BAL) may confirm the diagnosis in 15-50% of patients with PLCH. The presence of at least 5% CD1a-positive cells (Langerhans cells) in the BAL is highly suggestive of PLCH.

If bronchoscopic specimens do not provide confirmatory evidence for the diagnosis of PLCH, surgical lung biopsy may be needed (Figure 3).

Figure 3.

A high-power magnification view of PLCH histopathology demonstrating infiltration with Langerhans cells (characterized by pale staining cytoplasm and elongated nuclei with delicate folds and clefts and large nucleoli) and scattered eosinophils.

What pathology/cytology/genetic studies will be helpful in making or excluding the diagnosis of pulmonary Langerhans cell histiocytosis?

Immunohistochemical staining for CD1a antigen, S-100, and langerin are helpful in identifying Langerhans cells in the pathologic lesion. Recently, an activating BRAF V600E mutation has been identified in a subset of patients with PLCH.

If you decide the patient has pulmonary Langerhans cell histiocytosis, how should the patient be managed?

Patients diagnosed with PLCH who are still smoking cigarettes must cease smoking promptly. This is the most effective method of managing adult PLCH and often requires the use of nicotine replacement therapy along with other pharmacologic therapies (e.g., bupropion, varenicline) and counseling. Corticosteroid therapy, typically in the form of oral prednisone 40-60 mg per day with slow tapering over a course of several months, has been employed in some patients but with uncertain benefit and the associated well-known risks of long-term therapy including immunosuppression, osteoporosis, and metabolic effects. Chemotherapy agents such as 2-chlorodeoxyadenosine, (2-CDA or cladribine), vinblastine, cyclophosphamide, and methotrexate have also been used, but their therapeutic role in adult PLCH remains unclear. These agents are associated with myelosuppression as well as renal and hepatic toxicity. Recent identification of BRAF V600E mutation in some patients with PLCH has introduced the possibility of using targeted therapy with vemurafenib and other similar agents.

Lung transplantation is an option for patients with progressive pulmonary disease resulting in severe pulmonary impairment and symptoms. Recurrence of PLCH has been noted in 20 percent of patients who have undergone lung transplantation.

What is the prognosis for patients managed in the recommended ways?

With successful smoking cessation, most patients experience stabilization or improvement of their lung disease. Continuing exposure to cigarette smoke usually results in progressive lung disease with increasing risk of complications such as pulmonary hypertension, hypoxemia, and respiratory failure.

What other considerations exist for patients with pulmonary Langerhans cell histiocytosis?

Pulmonary hypertension in patients with PLCH may develop even in the absence of advanced lung disease and can be treated with vasodilator therapy, such as sildenafil or bosentan.

The recurrence rate in patients who experience spontaneous pneumothorax associated with PLCH is relatively high at about 60%. Pleurodesis, preferably surgical, is generally recommended to prevent recurrent pneumothorax.